Overwhelming Evidence Transplacental Transmission of Human Papillomavirus Primarily Causes Autism

Because the concordance rate between identical twins is only 88%, an environmental factor must cause autism spectrum disorder (ASD). Furthermore, when identical twins share ASD, it is to varying degrees suggesting different prenatal environments exist, which occurs when identical twins have separate placentas (~30% of the time). Placental inclusions are predictive of ASD along with excessive increases in extra-axial cerebral spinal fluid (CSF) detected by MRI in the brains of 6- and 12-month-old infants later diagnosed at 2 years with ASD. The human papillomavirus (HPV) can infect the trophoblast cells of placentas and transmit to the fetus where it infects the epithelial cells of the choroid plexus, a centrally located lining inside the brain responsible for producing CSF via the SLC4A10 gene product. HPV causes epigenetic changes, deletions, and duplications of genes, and besides its characteristic methylation patterns, the SLC4A10 gene was found to be increased in children with ASD. Moreover, male placentas implant close to the cervix (low-lying) three times more often than female placentas paralleling the ASD ratio of ~3:1 (boys to girls). Finally, the Australian HPV vaccination programme that began in 2007 might explain why the 0-4 yr. ASD incidence did not increase from 2010 to 2015.

Pyrroloquinoline Quinone Enhances Cognition of Neuroinflammatory Alzheimer’s Disease Mouse Model via Mitochondrial Biogenesis Regulation

Background: Mitochondrial biogenesis has been recently implicated to play an important role in Alzheimer’s disease (AD). Recently it has been reported that brains of AD patients show reduced expression in major genes and proteins such as PGC-1α involved in mitochondrial biogenesis. This led to the idea that enhancing mitochondrial biogenesis in AD, might represent a plausible strategy for AD treatment. Pyrroloquinoline quinone (PQQ) has been recently implicated in enhancing cognitive functions during aging; however, its effect on mitochondrial biogenesis in neuroinflammatory AD mouse model was not previously examined. Objective: The aim of this project was to test the cognitive enhancement effect of PQQ in a neuroinflammatory mouse model mimicking AD, and whether PQQ is able to activate mitochondrial biogenesis in brains of our AD mouse model. Methods: Neuroinflammatory AD mouse model was developed by Lipopolysaccharide (250 g kg-1 body weight, i.p) injection for 7 days, followed by daily PQQ treatment (10 mg kg-1 body weight) on days 4-7. Cognitive functions were assessed using Y-Maze, Water-Maze and object recognition tests. Neurodegeneration was evaluated using H&E. Finally, mitochondrial proteins were measured using immunohistochemistry. Results: PQQ treatment improved spatial recognition and working memory. PQQ treated mice brains showed decreased levels of neurodegeneration. Moreover, their brains showed greater amounts of both PGC-1α and the mitochondrial-membrane-bound protein cytochrome-c, indicating enhancement of mitochondrial biogenesis. Conclusion: This study demonstrates the ability of PQQ to improve memory in neuroinflammatory AD model via enhancing mitochondrial biogenesis, which may represent an alternative mechanistic approach for treating AD.

Chronic Unpredictable Stress Alters Brain Tryptophan Metabolism and Impairs Working Memory in Mice without Causing Depression-Like Behaviour

Chronic stress is a well-known risk factor in major depressive disorder and disrupts the kynurenine and serotonin pathways of tryptophan metabolism. Here, we characterize the temporal central and peripheral changes in tryptophan metabolism and concomitant depressive-like behavioural phenotype induced during the progression of chronic unpredictable stress (CUS). Mice were exposed to 0, 10, 20, or 30 days of CUS followed by a panel of behavioural assays to determine depressive-like phenotypes. Immediately after behavioural testing, plasma and brain tissue were collected for metabolic analysis. While anhedonia-like and anxiety-like behaviours were unaffected by stress, nesting behaviour and cognitive deficits became apparent in response to CUS exposure. While CUS caused a transient reduction in circulating quinolinic acid, no other tryptophan metabolites significantly changed in response to CUS. In the brain, tryptophan, kynurenine, picolinic acid, and 5-hydroxyindoleacetic acid concentrations were significantly elevated in CUS-exposed mice compared with non-stress control animals, while kynurenic acid, xanthurenic acid, and serotonin decreased in CUS-exposed mice. Metabolic turnover of serotonin to the major metabolite 5-hydroxyindoleacetic acid was markedly increased in response to CUS. These results suggest that CUS impairs hippocampal-dependent working memory and enhances nascent nesting behaviour in C57BL/6J male mice, and these behaviours are associated with increased brain kynurenine pathway metabolism leading to accumulation of picolinic acid and a significant reduction in serotonin levels.

Evaluation of BRAF Gene Status in Gliomas

Background: Development of different molecular markers has given a new insight in the glioma management. KIAA1549-BRAF gene fusion has a diagnostic and prognostic significance. Aim: The aim of this study was to determine the KIAA1549-BRAF gene fusion in glioma and their correlation with various clinical parameters. Material and Methods: Forty cases of glioma were studied for KIAA1549-BRAF gene fusion by reverse transcription-PCR (RT-PCR). Results: Overall, KIAA1549-BRAF gene fusion was found in 22% (9/40) cases of glioma. Children had higher KIAA1549-BRAF fusion (72%; 8/11) as compared to adults (10%; 3/29) and this difference was statistically significant. Cerebellar location of tumor was significantly associated with KIAA1549-BRAF fusion. KIAA1549-BRAF fusion was highest in pilocytic astrocytoma (89%), and this difference was statistically significant. Statistically significant difference was noted between KIAA1549-BRAF fusion expression and WHO grade I glioma. Conclusion: Overall, KIAA1549-BRAF gene fusion was found in 22% (9/40) cases of glioma. Childhood age, pilocytic astrocytoma histology, cerebellar location and WHO grade I tumor were significantly associated with KIAA1549-BRAF gene fusion.

Augmented Pain and Inflammation with Obesity: A Role for the Pro-Inflammatory Cytokine Visfatin

Obesity is associated with several co-morbidities including chronic pain. Systemic low-grade chronic inflammation and dysregulation of pro-inflammatory cytokines have been proposed to underlie these phenomena. This study characterized pain and inflammation, and levels of the pro-inflammatory cytokine visfatin, in a rodent model of obesity, and investigated whether treatment with the visfatin inhibitor, FK866, has anti-inflammatory and/or analgesic effects in normal and obese rats. The effects of pre-administration of FK866 (3, 10 mg/kg; i.p.) on carrageenan (3%; i.d. into the left paw)-induced thermal and mechanical hypersensitivity and paw oedema was measured in adult male Wistar rats fed a normal diet (ND) or high fat diet (HFD) for 12 weeks. HFD-fed rats displayed an increased sensitivity to acute mechanical nociceptive stimulation, and potentiated mechanical hyperalgesia and peripheral inflammation to carrageenan. Levels of circulating visfatin were increased in HFD-fed rats. Treatment with FK866, a visfatin inhibitor, was effective in reducing carrageenan-induced hyperalgesia and paw oedema in both ND-fed and HFD-fed rats. These data show that FK866 has anti-inflammatory and analgesic properties. The potentiated response to pain and inflammation, and elevated visfatin levels in HFD-fed rats supports the hypothesis that obesity is a chronic low-grade inflammatory disorder. Reversal of this co-morbidity by blocking visfatin may be a novel therapeutic strategy for managing pain with obesity.

Is Saline Injection a True Sham/Placebo Treatment in Randomized Controlled Trials? A Systematic Review

Objective: To explore whether saline is a real sham/placebo agent, or it has potential therapeutic effects when used as control treatment in randomized controlled trials for the management of discogenic low back pain. Methods: A comprehensive literature search was conducted investigating the effects of saline as a placebo in the treatment of chronic pain when administered into the intervertebral disc. Following stepwise filtering, selected articles were assessed for their levels of evidence, followed by a discussion of their contribution to the understanding of the role of saline in chronic pain management. Results: Out of 95 articles that described the administration of intradiscal saline solution used as a placebo for chronic pain management, 8 articles met all of the inclusion criteria. Their levels of evidence ranged from 1a to 4 (Oxford Centre CEBM). Intradiscal administration of saline solution was found to have measurable therapeutic benefits. In some studies, the pain relief was similar to that provided by local anaesthetics and steroids. Conclusion: Although the exact mechanism of the analgesic effects of saline is not clear, yet the use of intradiscal saline appears to have some analgesic benefits like local anaesthetics and steroids when used individually. Researchers should practice caution when designing RCTs using intradiscal saline injection as a sham/placebo treatment for the control arm or maybe, when possible, avoid the use of intradiscal saline injection as a sham treatment.

Brain Syndemics: Cognitive Deficit, Pathways of Interaction, and the Biology of Inequality

Children born into and raised in disadvantaged families tend to experience poorer health and more developmental delays, lower achievement, and a greater number of behavioural and emotional problems than children from wealthier homes. There is growing evidence that poverty and social inequality leave their imprint on brain structure as well. The brain exhibits considerable plasticity, one expression of which is shaped by the biology of inequality. A specific consequence is cognitive deficit found among children raised in poverty and subject to social discrimination. This paper argues that several pathways impacted by poverty, including chronic stress, malnutrition, exposure to heightened levels of air pollution, and other toxin exposures, syndemically link social inequality to underlying neural mechanisms and to suboptimal brain development and structure. These deficits need not be permanent and are reversible through urgently needed structural, socio-economic intervention.

In silico Analysis of Alkaloids for Therapeutic Use in Treatment of Alzheimer's Disease by Targeting Acetylcholinesterase Enzyme

Alzheimer’s is a progressive mental deterioration associated with the degeneration of the cognition activities and memory loss. It is considered to be a multifactorial disease. One of the causes of the Alzheimer’s disease is the low concentration of the neurotransmitter named acetylcholine (ACh) at the synaptic cleft. Thus, inhibitor of Acetylcholinesterase (AChE), an enzyme whose function is to degrade the acetylcholine, is proved to be a promising candidate to treat this disease. Among the inhibitors are the natural alkaloids that also have an inhibitory effect on the AChE. In this study we have focused on the simple derivates of beta carbolime (a group of alkaloids) and studied their interaction with AChE via rigid protein-ligand docking approach.

CIDP Masquerading as Mononeuritis Multiplex: The Value of MR Neurography

Background: We present two patients with the Lewis-Sumner variant of chronic inflammatory demyelinating polyradiculoneuropathy (CIDP), charting the diagnostic challenge posed by their clinical presentation and electrodiagnostic findings. The learning points center on the use of magnetic resonance imaging (MRI) in establishing a definitive diagnosis when clinical and neurophysiology data do not otherwise add up. Cases: The first patient presented with slowly progressive asymmetric distal weakness of the lower limbs with wasting, weakness, areflexia and numbness on examination. The second patient experienced stepwise asymmetric hand/forearm weakness with deformity and areflexia, plus mild distal sensory impairment. Neurophysiological studies for both patients were initially most suggestive of mononeuritis multiplex, with no evidence of demyelination. Conclusion: The possibility of asymmetric or multifocal CIDP, the Lewis-Sumner variant, should not be forgotten in suspected mononeuritis multiplex and the value of MRI in such cases is discussed.

DNA Methyltransferase Inhibitor Successfully Treats Obsessive-Compulsive Disorder in Various Mouse Models

Mental health disorders are manifested in families yet cannot be fully explained by classical Mendelian genetics. Changes in gene expression via epigenetics present a plausible mechanism. Anxiety often leads to avoidant behaviours, which upon repetition may become habitual, maladaptive, and resistant to extinction as observed in obsessive-compulsive disorders (OCD). Psychophysical models of OCD propose that anxiety (amygdala) and habits (dorsolateral striatum, DLS) may be causally linked. The amygdala activates spiny projection neurons in the DLS. Repetitive amygdala terminal stimulation in the DLS elicits long-term OCD-like behaviour in mice associated with circuitry changes and gene methylation-mediated decrease in protein phosphatase 1 (PP1). Treatment of OCD-like grooming behaviour in Slitrk5, SAPAP3, and laser-stimulated mice with one dose of RG108 (DNA methyltransferase inhibitor), leads to marked symptom improvement lasting for at least one week as well as a complete reversal of abnormal changes in the circuitry and PP1 activity.